Abstract Aim: The aim of this study was to determine whether GSH-C4, a hydrophobic glutathione derivative, affects in vitro and in vivo influenza virus infection by interfering with redox-sensitive intracellular pathways involved in the maturation of viral hemagglutinin (HA). Results: GSH-C4 strongly inhibited influenza A virus replication in cultured cells and in lethally infected mice, where it also reduced lung damage and mortality. In cell-culture studies, GSH-C4 arrested viral HA folding; the disulfide-rich glycoprotein remained in the endoplasmic reticulum as a reduced monomer instead of undergoing oligomerization and cell plasma-membrane insertion. HA maturation depends on the host-cell oxidoreductase, protein disulfide isomerase (PDI), whose activity in infected cells is probably facilitated by virus-induced glutathione depletion. By correcting this deficit, GSH-C4 increased levels of reduced PDI and inhibited essential disulfide bond formation in HA. Host-cell glycoprotein expression in uninfected cells was unaffected by glutathione, which thus appears to act exclusively on glutathione-depleted cells. Innovation: All currently approved anti-influenza drugs target essential viral structures, and their efficacy is limited by toxicity and by the almost inevitable selection of drug-resistant viral mutants. GSH-C4 inhibits influenza virus replication by modulating redox-sensitive pathways in infected cells, without producing toxicity in uninfected cells or animals. Novel anti-influenza drugs that target intracellular pathways essential for viral replication ("cell-based approach") offer two important potential advantages: they are more difficult for the virus to adapt to and their efficacy should not be dependent on virus type, strain, or antigenic properties. Conclusion: Redox-sensitive host-cell pathways exploited for viral replication are promising targets for effective anti-influenza strategies. Antioxid. Redox Signal. 15, 000-000.
Sgarbanti, R., Nencioni, L., Amatore, D., Coluccio, P., Fraternale, A., Sale, P., et al. (2011). Redox Regulation of the Influenza Hemagglutinin Maturation Process: A New Cell-Mediated Strategy for Anti-Influenza Therapy. ANTIOXIDANTS & REDOX SIGNALING, 15(3), 593-606.
|Tipologia:||Articolo su rivista|
|Citazione:||Sgarbanti, R., Nencioni, L., Amatore, D., Coluccio, P., Fraternale, A., Sale, P., et al. (2011). Redox Regulation of the Influenza Hemagglutinin Maturation Process: A New Cell-Mediated Strategy for Anti-Influenza Therapy. ANTIOXIDANTS & REDOX SIGNALING, 15(3), 593-606.|
|Settore Scientifico Disciplinare:||Settore BIO/10|
|Revisione (peer review):||Sì, ma tipo non specificato|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1089/ars.2010.3512|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||19-mag-2011|
|Titolo:||Redox Regulation of the Influenza Hemagglutinin Maturation Process: A New Cell-Mediated Strategy for Anti-Influenza Therapy|
|Autori:||Sgarbanti, R; Nencioni, L; Amatore, D; Coluccio, P; Fraternale, A; Sale, P; Mammola, CL; Carpino, G; Gaudio, E; Magnani, M; Ciriolo, M R; Garaci, E; Palamara, AT|
|Appare nelle tipologie:||01 - Articolo su rivista|